Project Summary: Inflammation plays a role in the response to pathogens and in the etiology of chronic diseases including atherosclerosis, diabetes and Alzheimer?s disease. Not surprisingly, strategies to inhibit the inflammatory response and promote resolution of inflammation are being explored for therapeutic benefit. Recent studies have demonstrated that the response of immune cells to pro- and anti-inflammatory signals is associated with changes in lipid metabolism. Activation of toll-like receptor 4 (TLR4) in macrophages leads to a rapid and transient inhibition of fatty acid synthesis that is followed by a later increase in the synthesis of long chain unsaturated fatty acids. Importantly, fatty acid synthesis at later stages of the inflammatory response has been suggested to play a role in resolving inflammation. The signaling pathways that couple lipid metabolism to inflammation, however, are still being defined. The liver X receptors LXR? and LXR? are members of the nuclear hormone receptor superfamily of ligand activated transcription factors that control genetic networks involved in fatty acid and cholesterol metabolism. We have uncovered a previously unexplored link between LXR activity and inflammatory signaling. Our data indicates that TLR activation leads to up-regulation of LXR expression in a type I interferon- dependent manner at relatively late stages of the inflammatory response. Signal transducer and activator of transcription 1 (STAT1), an interferon stimulated transcription factor, appears to be necessary for the LXR induction. LXRs are subsequently required for the proper shutdown of type I interferon stimulated gene expression. We hypothesize that LXRs interfere with STAT1 transcriptional activity and contribute to a negative feedback loop that plays a role in resolution of the inflammatory response. Concurrently there is an LXR-dependent increase in gene expression associated with the generation of long chain unsaturated fatty acids with reported anti-inflammatory activity. We propose that the effect of LXRs on fatty acid synthesis requires cooperation with sterol regulatory element binding protein 1 (SREBP1), a second transcriptional regulator of fatty acid synthesis. Furthermore we propose that SREBP1 activity can be regulated via interferon-dependent control of the mammalian target of rapamycin (mTOR). Thus type I interferons integrate LXR and mTOR signaling pathways to establish a specific gene expression network that contributes to resolution of the inflammatory response. The goals of the proposed studies are to define the pathway that controls the inflammation-dependent activation of fatty acid synthesis and to determine the LXR-dependent pathway that shuts down type I interferon signaling. We anticipate that these studies will define a novel interface between lipid metabolism and the inflammatory response and may provide new approaches to promote the resolution of inflammation.